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  • Review Article
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Differences in hematotoxicity between male and female patients with Hodgkin lymphoma and other malignancies

Nature Clinical Practice Oncology volume 5, pages 316–323 (2008)Cite this article

Abstract

With improved treatment strategies and prognosis for patients with Hodgkin lymphoma (HL), interest has increasingly focused on high-risk groups. These groups include a small proportion of patients who experience relapse or who have primary refractory disease despite state-of-the-art treatment. Although many research efforts have been made in this field, specific biological markers that reliably predict unfavorable outcome during first-line treatment are lacking. Recent analyses in HL and other malignancies, however, have demonstrated an important impact of patient-related factors, such as individual differences in hematologic toxicity and drug metabolism, on disease outcome. A different cytochrome enzyme status and slower drug clearance in female patients, resulting in higher systemic toxicity and effectiveness of treatment, indicate that sex-specific aspects are important. In this Review, we discuss the current data on hematotoxicity among male and female patients with HL and other malignancies. In addition, we highlight the potential causes of hematotoxicity and its impact on treatment outcome and the role of future strategies.

Key Points

  • Results from studies of patients with Hodgkin lymphoma and other malignancies report a generally more favorable outcome in female patients with cancer than in male patients with cancer

  • The treatment-induced hematologic toxicity in female patients is related to greater efficacy of chemotherapy and might be caused by a different enzyme status and slower drug clearance that results in better systemic dosing of cytostatic drugs

  • Genetic polymorphisms in genes encoding enzymes are known to produce individual differences in drug toxicity, and the expression and activity of enzymes are influenced by factors such as gender, smoking, steroid hormones and coadministration of other drugs

  • The implementation of gender-adapted and hematotoxocity-adapted treatment strategies, based on individual pharmacokinetics, might result in more uniform toxicity and better treatment outcome in future studies

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Figure 1: Analysis of 4,626 patients with Hodgkin lymphoma.
Figure 2: A comparison of the survival of 648 male and 358 female patients with small-cell lung cancer.

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References

  1. Engert A et al. (2007) Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial. J Clin Oncol 25: 3495–3502

    Article  CAS  Google Scholar 

  2. Engert et al. (2003) Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 21: 3601–3608

    Article  Google Scholar 

  3. Diehl V et al. (2003) Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 348: 2386–2395

    Article  CAS  Google Scholar 

  4. Klimm B et al. (2005) Current treatment and immunotherapy of Hodgkin's lymphoma. Haematologica 90: 1680–1692

    CAS  PubMed  Google Scholar 

  5. Klimm B et al. (2005) Role of hematotoxicity and sex in patients with Hodgkin's lymphoma: an analysis from the German Hodgkin Study Group. J Clin Oncol 23: 8003–8011

    Article  CAS  Google Scholar 

  6. Hasenclever D and Diehl V (1998) A prognostic score for advanced Hodgkin's disease: International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 339: 1506–1514

    Article  CAS  Google Scholar 

  7. Smith RS et al. (2003) Prognostic factors for children with Hodgkin's disease treated with combined-modality therapy. J Clin Oncol 21: 2026–2033

    Article  Google Scholar 

  8. Gobbi PG et al. (2001) Comparison of prognostic models in patients with advanced Hodgkin disease: promising results from integration of the best three systems. Cancer 91: 1467–1478

    Article  CAS  Google Scholar 

  9. Maucort-Boulch D et al. (2007) Predictive and discriminating three-risk-group prognostic scoring system for staging Hodgkin lymphomas. Cancer 109: 256–264

    Article  Google Scholar 

  10. Hasenclever D (2002) The disappearance of prognostic factors in Hodgkin's disease. Ann Oncol 13 (Suppl 1): 75–78

    Article  Google Scholar 

  11. Arbeitsgemeinschaft Bevölkerungsbezogener Krebsregister in Deutschland, in Zusammenarbeit mit dem Robert-Koch-Institut. Krebs in Deutschland, Häufigkeiten und Trends. [http://www.rki.de] (accessed 12 March 2008)

  12. Liu S et al. (2000) Time trends and sex patterns in Hodgkin's disease incidence in Canada, 1970–1995. Can J Public Health 91: 188–192

    CAS  PubMed  Google Scholar 

  13. Jeffery GM et al. (1989) A risk factor for relapse in Hodgkin's disease: female gender? Hematol Oncol 7: 345–353

    Article  CAS  Google Scholar 

  14. Flavell KJ et al. (2003) The effect of Epstein–Barr virus status on outcome in age- and sex-defined subgroups of patients with advanced Hodgkin's disease. Ann Oncol 14: 282–290

    Article  CAS  Google Scholar 

  15. Brosteanu O et al. (2004) Low acute hematological toxicity during chemotherapy predicts reduced disease control in advanced Hodgkin's disease. Ann Hematol 83: 176–182

    Article  CAS  Google Scholar 

  16. MacLeod SL et al. (2000) Cancer therapy and polymorphisms of cytochromes P450. Clin Chem Lab Med 38: 883–887

    Article  CAS  Google Scholar 

  17. Cotreau MM et al. (2005) The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet 44: 33–60

    Article  CAS  Google Scholar 

  18. Catovsky D et al. (1989) Prognostic factors in chronic lymphocytic leukaemia: the importance of age, sex and response to treatment in survival: a report from the MRC CLL 1 trial. MRC Working Party on Leukaemia in Adults. Br J Haematol 72: 141–149

    Article  CAS  Google Scholar 

  19. Wakelee HA et al. (2006) Survival differences by sex for patients with advanced non-small cell lung cancer on Eastern Cooperative Oncology Group Trial 1594. J Thorac Oncol 1: 441–446

    Article  Google Scholar 

  20. Singh S et al. (2005) Influence of sex on toxicity and treatment outcome in small-cell lung cancer. J Clin Oncol 23: 850–856

    Article  Google Scholar 

  21. Marosi C (2006) Gender aspects of treatment and drug related toxicity in medical oncology. Wien Med Wochenschr 156: 534–540

    Article  Google Scholar 

  22. Molica S et al. (2005) A gender-based score system predicts the clinical outcome of patients with early B-cell chronic lymphocytic leukemia. Leuk Lymphoma 46: 553–560

    Article  Google Scholar 

  23. Milano G et al. (1992) Influence of sex and age on fluorouracil clearance. J Clin Oncol 10: 1171–1175

    Article  CAS  Google Scholar 

  24. Stein BN et al. (1995) Age and sex are independent predictors of 5-fluorouracil toxicity: analysis of a large scale phase III trial. Cancer 75: 11–17

    Article  CAS  Google Scholar 

  25. Zalcberg J et al. (1998) Haematological and non-haematological toxicity after 5-fluorouracil and leucovorin in patients with advanced colorectal cancer is significantly associated with gender, increasing age and cycle number: Tomudex International Study Group. Eur J Cancer 34: 1871–1875

    Article  CAS  Google Scholar 

  26. Sloan JA et al. (2002) Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol 20: 1491–1498

    Article  CAS  Google Scholar 

  27. Dobbs NA et al. (1995) Gender affects doxorubicin pharmacokinetics in patients with normal liver biochemistry. Cancer Chemother Pharmacol 36: 473–476

    Article  CAS  Google Scholar 

  28. Kaul S et al. (1996) Effects of gender, age, and race on the pharmacokinetics of etoposide after intravenous administration of etoposide phosphate in cancer patients. Semin Oncol 23: 23–29

    CAS  PubMed  Google Scholar 

  29. Evans WE and Relling MV (2004) Moving towards individualized medicine with pharmacogenomics. Nature 429: 464–468

    Article  CAS  Google Scholar 

  30. Tsalic M et al. (2003) Severe toxicity related to the 5-fluorouracil/leucovorin combination (the Mayo Clinic regimen): a prospective study in colorectal cancer patients. Am J Clin Oncol 26: 103–106

    CAS  PubMed  Google Scholar 

  31. Van Kuilenburg AB et al. (2002) Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: high prevalence of the IVS14+1g>a mutation. Int J Cancer 101: 253–258

    Article  CAS  Google Scholar 

  32. Van Kuilenburg AB (2004) Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer 40: 939–950

    Article  CAS  Google Scholar 

  33. Van Kuilenburg AB et al. (2007) Increased dihydropyrimidine dehydrogenase activity associated with mild toxicity in patients treated with 5-fluorouracil and leucovorin. Eur J Cancer 43: 459–465

    Article  CAS  Google Scholar 

  34. Van Kuilenburg AB et al. (2007) HPLC-electrospray tandem mass spectrometry for rapid determination of dihydropyrimidine dehydrogenase activity. Clin Chem 53: 528–530

    Article  CAS  Google Scholar 

  35. Ploylearmsaeng SA et al. (2006) How may anticancer chemotherapy with fluorouracil be individualised? Clin Pharmacokinet 45: 567–592

    Article  CAS  Google Scholar 

  36. Davis M (2005) Gender differences in p-glycoprotein: drug toxicity and response. J Clin Oncol 23: 6439–6440

    Article  Google Scholar 

  37. Rousseau A and Marquet P (2002) Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs. Fundam Clin Pharmacol 16: 253–262

    Article  CAS  Google Scholar 

  38. Yule SM et al. (2004) Cyclophosphamide metabolism in children with non-Hodgkin's lymphoma. Clin Cancer Res 10: 455–460

    Article  CAS  Google Scholar 

  39. Ferreri AJ et al. (2004) Area under the curve of methotrexate and creatinine clearance are outcome-determining factors in primary CNS lymphomas. Br J Cancer 90: 353–358

    Article  CAS  Google Scholar 

  40. Wilde S et al. (2007) Population pharmacokinetics of the BEACOPP polychemotherapy regimen in Hodgkin's lymphoma and its effect on myelotoxicity. Clin Pharmacokinet 46: 319–333

    Article  CAS  Google Scholar 

  41. Wilson WH et al. (2002) Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood 99: 2685–2693

    Article  CAS  Google Scholar 

  42. Carde P et al. (2002) Early response to chemotherapy: A surrogate for final outcome of Hodgkin's disease patients that should influence initial treatment length and intensity? Ann Oncol 13 (Suppl 1): 86–91

    Article  Google Scholar 

  43. Hasenclever D (2004) How to minimize over-treatment: model based design of studies on response adapted therapy (RAT). Eur J Haematol 73: 16a

    Google Scholar 

  44. Hutchings M et al. (2006) FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107: 52–59

    Article  CAS  Google Scholar 

  45. Zanotti R et al. (2002) Serum levels of soluble CD30 improve International Prognostic Score in predicting the outcome of advanced Hodgkin's lymphoma. Ann Oncol 13: 1908–1914

    Article  CAS  Google Scholar 

  46. Rosenwald A (2003) DNA microarrays in lymphoid malignancies. Oncology (Williston Park) 17: 1743–1748

    Google Scholar 

  47. Rosenwald A et al. (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346: 1937–1947

    Article  Google Scholar 

  48. Hans CP et al. (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103: 275–282

    Article  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. B Klimm is a Medical Doctor in the Department of Internal Medicine, and A Engert is Professor for Internal Medicine, at the University Hospital Cologne, Cologne, Germany.,

    Beate Klimm & Andreas Engert

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  1. Beate Klimm
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  2. Andreas Engert
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Correspondence to Andreas Engert.

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The authors declare no competing financial interests.

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Klimm, B., Engert, A. Differences in hematotoxicity between male and female patients with Hodgkin lymphoma and other malignancies. Nat Rev Clin Oncol 5, 316–323 (2008). https://doi.org/10.1038/ncponc1124

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